NOD mice spontaneously develop insulin-dependent diabetes mellitus (IDDM) secondary to immunologically-mediated beta cell destruction in pancreatic islets. These mice exhibit an increase in the amount of mesangial matrix before diabetes mellitus occurs and are therefore "prone to glomerulosclerosis". Shortly after the appearance of diabetes, there is an accentuation of the renal lesions consisting of mesangial sclerosis, thickening of glomerular basement membranes, and albuminuria. Morphometric analysis showed that the kidney weight and glomerular size were increased in diabetic mice, compared to non-diabetic mice, and that the ratio glomerular volume/kidney weight was elevated in diabetic mice. We explored by competitive PCR of isolated glomeruli the glomerular turnover of the extracellular matrix components. Prior to the appearance of diabetes the levels of type IV collagen mRNA were 3-4 times higher than in SJL mice who have normal glomeruli. In addition the NOD mice had fewer glomeruli than the SLJ and those were larger. Therefore the NOD strain has a propensity to develop sclerosis irrespective of diabetes which is underlied by an abnormal level of expression of basement membrane gene expression and by a reduced number of glomeruli. We are now investigating whether the occurrence of diabetes mellitus leads to an upregulation of the collagens gene expression. This study is the first to establish that there is a different baseline expression of type IV collagen in different strains of mice and may be directly applicable to man since it is well known that the susceptibility to progressive glomerulosclerosis varies according to the ethnical background.